Oxidative stress and inflammation play critical roles in the development of diabetes and its complications. Recent studies provided compelling evidence that the newly discovered lipid signaling system (ie, the endocannabinoid system) may significantly influence reactive oxygen species production, inflammation, and subsequent tissue injury, in addition to its well-known metabolic effects and functions. The endocannabinoid (EC) system includes the endocannabinoids (two main ECs are anandamide and 2-arachidonoyl glycerol), their specific G protein-coupled receptors (cannabinoid-1 receptor, cannabinoid-2 receptor) and their metabolizing enzymes (fatty acid hydrolase and monoacylglycerol lipase). The modulation of the activity of this system holds tremendous therapeutic potential in a wide range of diseases, ranging from cancer, pain, neurodegenerative, and cardiovascular diseases to obesity and metabolic syndrome, diabetes, and diabetic complications.

This review focuses on the role of the endocannabinoid system in primary diabetes and its effects on various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system. The authors are discussing the opposing role of the two cannabinoid receptors` activation on these disease processes. Cannabinoid-1 receptor activation may indirectly (via its metabolic consequences) or directly enhance diabetes-associated inflammation and ROS generation, promoting tissue injury and the development of diabetic complications. In contrast, cannabinoid-2 receptor stimulation may exert beneficial effects against various diabetic complications by attenuating high glucose–induced endothelial cell activation and inflammatory response; chemotaxis, transmigration, adhesion, and activation of inflammatory cells; and subsequent proinflammatory responses and ROS generation. The therapeutic potential of targeting the endocannabinoid system and certain plant-derived cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabivarin, which are devoid of psychotropic effects and possess potent anti-inflammatory and/or antioxidant properties, in diabetes and diabetic complications is also discussed.